The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells

Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention

Systematic Investigation of the Permeability of Androgen Receptor PROTACs.

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed.This work was funded by Alzheimer’s Research UK (grant: ARUK-2015DDI-CAM), with support from the ALBORADA Trust. The ALBORADA Drug Discovery Institute is core funded by Alzheimer’s Research UK (registered charity No. 1077089 and SC042474)

Estimation of Activity Related Energy Expenditure and Resting Metabolic Rate in Freely Moving Mice from Indirect Calorimetry Data

Physical activity (PA) is a main determinant of total energy expenditure (TEE) and has been suggested to play a key role in body weight regulation. However, thus far it has been challenging to determine what part of the expended energy is due to activity in freely moving subjects. We developed a computational method to estimate activity related energy expenditure (AEE) and resting metabolic rate (RMR) in mice from activity and indirect calorimetry data. The method is based on penalised spline regression and takes the time dependency of the RMR into account. In addition, estimates of AEE and RMR are corrected for the regression dilution bias that results from inaccurate PA measurements. We evaluated the performance of our method based on 500 simulated metabolic chamber datasets and compared it to that of conventional methods. It was found that for a sample time of 10 minutes the penalised spline model estimated the time-dependent RMR with 1.7 times higher accuracy than the Kalman filter and with 2.7 times higher accuracy than linear regression. We assessed the applicability of our method on experimental data in a case study involving high fat diet fed male and female C57Bl/6J mice. We found that TEE in male mice was higher due to a difference in RMR while AEE levels were similar in both groups, even though female mice were more active. Interestingly, the higher activity did not result in a difference in AEE because female mice had a lower caloric cost of activity, which was likely due to their lower body weight. In conclusion, TEE decomposition by means of penalised spline regression provides robust estimates of the time-dependent AEE and RMR and can be applied to data generated with generic metabolic chamber and indirect calorimetry set-ups

The ethnoecology of Caiçara metapopulations (Atlantic Forest, Brazil): ecological concepts and questions

The Atlantic Forest is represented on the coast of Brazil by approximately 7,5% of remnants, much of these concentrated on the country's SE coast. Within these southeastern remnants, we still find the coastal Caiçaras who descend from Native Indians and Portuguese Colonizers. The maintenance of such populations, and their existence in spite of the deforestation that occurred on the Atlantic Forest coast, deserves especial attention and analysis. In this study, I address, in particular, the Caiçaras who live on the coast of São Paulo and Rio de Janeiro States, illustrating with examples of coastal inhabitants from other areas, such as Bahia State (NE coast) and of other forested areas (riverine caboclos of the Amazon). The major focus of this study, based on previous research, performed since 1986 in several populations or villages of the Atlantic Forest coast, is to understand the resilience of the Caiçaras, which is analyzed using ecological concepts, such as metapopulation, resilience and adaptive cycles. The Caiçara populations are located on islands (Búzios, Comprida, Grande, Ilhabela, Jaguanum, Gipóia) and on the coast (Bertioga, Puruba, Picinguaba, among others). Information gathered about the Caiçaras regarding the economic cycles of the local regions, along with ecological, historical and economic data available, are used to understand such resilience, and are complemented with comparative examples from the Brazilian Amazon and with variables such as the local restrictions imposed by environmental governmental agencies

Daptomycin antimicrobial activity tested against methicillin-resistant staphylococci and vancomycin-resistant enterococci isolated in European medical centers (2005)

BACKGROUND: Daptomycin is a cyclic lipopeptide with potent activity and broad spectrum against Gram-positive bacteria currently used for the treatment of complicated skin and skin structure infections and bacteremia, including right sided endocarditis. We evaluated the in vitro activity of this compound and selected comparator agents tested against clinical strains of staphylococci and enterococci collected in European medical centers in 2005. METHODS: A total of 4,640 strains from 23 medical centers located in 10 European countries, Turkey and Israel (SENTRY Program platform) were tested for susceptibility by reference broth microdilution methods according to Clinical and Laboratory Standards Institute guidelines and interpretative criteria. Mueller-Hinton broth was supplemented to 50 mg/L Ca(++ )for testing daptomycin. Results for oxacillin (methicillin)-resistant staphylococci and vancomycin-resistant enterococci were analyzed separately. RESULTS: Oxacillin resistance rates among Staphylococcus aureus varied from 2.1% in Sweden to 42.5% in the United Kingdom (UK) and 54.7% in Ireland (29.1% overall), while vancomycin resistance rates varied from 0.0% in France, Sweden and Switzerland to 66.7% in the UK and 71.4% in Ireland among Enterococcus faecium (17.9% overall). All S. aureus strains were inhibited at daptomycin MIC of 1 mg/L (MIC(50/90), 0.25/0.5 mg/L; 100.0% susceptible) and only one coagulase-negative staphylococci strain (0.1%) showed an elevated (>1 mg/L) daptomycin MIC value (4 mg/L). Among E. faecalis (MIC(50/90), 0.5/1 mg/L; 100% susceptible) the highest daptomycin MIC value was 2 mg/L; while among E. faecium (MIC(50/90), 2/4 mg/L; 100% susceptible) the highest MIC result was 4 mg/L. CONCLUSION: Daptomycin showed excellent in vitro activity against staphylococci and enterococci collected in European medical centers in 2005 and resistance to oxacillin, vancomycin or quinupristin/dalfopristin did not compromise its activity overall against these pathogens. Based on these results and those of previous publications, daptomycin appears to be an excellent therapeutic option for serious infections caused by oxacillin-resistant staphylococci and vancomycin-resistant enterococci in Europe

Antimalarial Therapy Selection for Quinolone Resistance among Escherichia coli in the Absence of Quinolone Exposure, in Tropical South America

BACKGROUND: Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use. METHODS: Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant gram-negative bacilli (GNB). Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR) mutations. RESULTS: In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p<0.01). Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine. CONCLUSIONS: In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas